{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T17:08:27Z","timestamp":1791306507099,"version":"4.3.1"},"reference-count":42,"publisher":"The Company of Biologists","issue":"18","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,9,15]]},"abstract":"<jats:p>The enteric nervous system (ENS) develops from neural crest cells (NCCs)that enter the foregut and hindgut to become enteric neural-crest-derived cells (ENCCs). When these cells of neural crest origin fail to colonize the terminal hindgut, this aganglionic region becomes non-functional and results in a condition in humans known as Hirschsprung's disease (HSCR). One of the genes associated with HSCR is endothelin receptor type B (Ednrb). To study the development of colonic aganglionosis we have utilized a novel knockout mouse (Ednrbflex3\/flex3), in which the expression of a null Ednrb allele and YFP is confined to NCCs. We have identified two primary cellular defects related to defective EDNRB signaling. First, ENCC advance in Ednrbflex3\/flex3 embryos is delayed shortly after NCCs enter the gut. Apart from this early delay, Ednrbflex3\/flex3 ENCCs advance normally until reaching the proximal colon. Second, as Ednrbflex3\/flex3 ENCCs reach the colon at E14.5, they display migratory defects, including altered trajectories and reduced speed, that are not dependent on proliferation or differentiation. We constructed grafts to test the ability of donor ENCCs to invade a recipient piece of aganglionic colon. Our results indicate that the age of the recipient, and not the age or genotype of donor ENCCs, determines whether the colon is invaded. We identify changes in laminin expression that are associated with the failure of ENCCs to invade recipient tissue. Together,our data suggest that a defect in pre-enteric Ednrbflex3\/flex3 NCCs results in delayed colonic arrival,which, due to environment changes in the colon, is sufficient to cause aganglionosis.<\/jats:p>","DOI":"10.1242\/dev.031302","type":"journal-article","created":{"date-parts":[[2009,8,21]],"date-time":"2009-08-21T18:01:40Z","timestamp":1250877700000},"page":"3195-3203","source":"Crossref","is-referenced-by-count":105,"title":["Age-dependent changes in the gut environment restrict the invasion of the hindgut by enteric neural progenitors"],"prefix":"10.1242","volume":"136","author":[{"given":"Noah R.","family":"Druckenbrod","sequence":"first","affiliation":[{"name":"Department of Anatomy and Neuroscience Training Program, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA."},{"name":"Department of Neurology, Harvard Medical School, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miles L.","family":"Epstein","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neuroscience Training Program, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042621410244100_REF1","unstructured":"Alzahem, A. M. and Cass, D. T. (2008). Animal Models of Aganglionosis in Hirschsprung\u0301s Disease and Allied Disorders (ed. A. M. Holschneider and P. Puri), pp.51-58. New York: Springer."},{"key":"2021042621410244100_REF2","doi-asserted-by":"crossref","unstructured":"Anderson, R. B., Newgreen, D. F. and Young, H. M.(2006). Neural crest and the development of the enteric nervous system. Adv. Exp. Med. Biol.589,181-196.","DOI":"10.1007\/978-0-387-46954-6_11"},{"key":"2021042621410244100_REF3","doi-asserted-by":"crossref","unstructured":"Bagnato, A., Rosano, L., Spinella, F., Di Castro, V., Tecce, R. and Natali, P. G. (2004). Endothelin B receptor blockade inhibits dynamics of cell interactions and communications in melanoma cell progression. Cancer Res.64,1436-1443.","DOI":"10.1158\/0008-5472.CAN-03-2344"},{"key":"2021042621410244100_REF4","doi-asserted-by":"crossref","unstructured":"Barlow, A., de Graaff, E. and Pachnis, V.(2003). Enteric nervous system progenitors are coordinately controlled by the G protein-coupled receptor EDNRB and the receptor tyrosine kinase RET. Neuron40,905-916.","DOI":"10.1016\/S0896-6273(03)00730-X"},{"key":"2021042621410244100_REF5","doi-asserted-by":"crossref","unstructured":"Barlow, A. J., Wallace, A. S., Thapar, N. and Burns, A. J.(2008). Critical numbers of neural crest cells are required in the pathways from the neural tube to the foregut to ensure complete enteric nervous system formation. Development135,1681-1691.","DOI":"10.1242\/dev.017418"},{"key":"2021042621410244100_REF6","doi-asserted-by":"crossref","unstructured":"Baynash, A. G., Hosoda, K., Giaid, A., Richardson, J. A., Emoto,N., Hammer, R. E. and Yanagisawa, M. (1994). Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons. 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Inability of neural crest cells to colonize the presumptive aganglionic bowel of ls\/ls mutant mice: requirement for a permissive microenvironment. J. Comp. Neurol.255,425-438.","DOI":"10.1002\/cne.902550309"},{"key":"2021042621410244100_REF22","doi-asserted-by":"crossref","unstructured":"Jiang, X., Rowitch, D. H., Soriano, P., McMahon, A. P. and Sucov, H. M. (2000). Fate of the mammalian cardiac neural crest. Development127,1607-1616.","DOI":"10.1242\/dev.127.8.1607"},{"key":"2021042621410244100_REF23","doi-asserted-by":"crossref","unstructured":"Kapur, R. P., Livingston, R., Doggett, B., Sweetser, D. A.,Siebert, J. R. and Palmiter, R. D. (1996). Abnormal microenvironmental signals underlie intestinal aganglionosis in Dominant megacolon mutant mice. Dev. Biol.174,360-369.","DOI":"10.1006\/dbio.1996.0080"},{"key":"2021042621410244100_REF24","doi-asserted-by":"crossref","unstructured":"Lahav, R. (2005). 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L., Woodward, M. N., Kenny, S. E., Lloyd, D. A.,Vaillant, C. R. and Edgar, D. H. (2002). Localization and endothelin-3 dependence of stem cells of the enteric nervous system in the embryonic colon. J. Pediatr. Surg.37,145-150.","DOI":"10.1053\/jpsu.2002.30239"},{"key":"2021042621410244100_REF34","doi-asserted-by":"crossref","unstructured":"Simpson, M. J., Zhang, D. C., Mariani, M., Landman, K. A. and Newgreen, D. F. (2007). Cell proliferation drives neural crest cell invasion of the intestine. Dev. Biol.302,553-568.","DOI":"10.1016\/j.ydbio.2006.10.017"},{"key":"2021042621410244100_REF35","doi-asserted-by":"crossref","unstructured":"Srinivas, S., Watanabe, T., Lin, C. S., William, C. M., Tanabe,Y., Jessell, T. M. and Costantini, F. (2001). Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev. 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